Development of an infection detecting wound dressing

Infection is the primary cause of complications following a burn injury. Even a small hot water scalds can become infected, which can lead to a great increase in pain, delayed healing, increased scarring, and a greater time in treatment (including antibiotic usage and surgery). This not only undermines the outcome for patients, but also increases costs to the NHS related to treatment, but also patients, in terms of days off work, travel to hospital, and related loss of income. In rare cases infection can lead to death, particularly in large and deep burns and even in children with small burns, via complications such as toxic shock syndrome.

Despite the importance of identifying infection, this currently remains a major challenge for clinicians. Much of the difficulty arises from the fact that the symptoms of infection in burn patients can be very difficult to distinguish from other symptoms arising from inflammatory response to the burn itself, as well as other illness such as cold, sore throat etc. Because of these challenges, the standard methods that clinicians use to diagnose infection under other conditions are of limited value in treating burns patients. The situation is further complicated by the fact that most wounds have normal background level of bacteria, which does not need to be treated unless bacteria reach a certain level at which they begin to cause harm. However, clinicians may wait ~3 days to confirm the presence of bacteria in a wound, but these tests do not distinguish between beginning background levels and those representative of infection. Collectively, these limitations can also lead to patients being 'over treated', resulting in over and unnecessary prescription of antibiotics, dressing changes (which are often painful and may increase the risk of scarring), and extended hospital stay.

The dressing being developed in this research programme indicates critical bacterial infection within a burn wound without the need to remove it. The dressing will signal infection by a simple colour change, that occurs when clinically relevant bacteria in the wound reach a level at which treatment is necessary. This can be used by clinicians directly at the patients bedside to provide more accurate and more effective treatment. In doing so our technology would not only improve outcomes for patients, but also reduce NHS costs and unnecessary antibiotic use.

NEED:140,000 patients with burns attend English and Welsh A&Es every year. Infection, a major cause of morbidity and mortality in patients with burn injuries, is implicated in ~32% of associated complications. However, diagnosis of infection in burn patients is problematic, with standard indicators of little value and clinicians routinely waiting 3 days for confirmatory tests. This clinical bottleneck undermines patient care, clinical outcomes and contributes to the inappropriate use of antibiotics and over treatment as well as missed infection diagnosis.

SOLUTION & RATIONALE: We have developed an infection responsive wound dressing which gives a clear visual indication of wound infection, directly at point-of-care. This technology responds to key cytotoxic virulence factors from predominant burn wound pathogens: Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecalis, ("SPE-group"; up to 80% of infections). Colour change is triggered at bacterial concentrations two orders of magnitude lower than their cytotoxicity threshold, providing early warning before major tissue damage can occur, whilst distinguishing invasive infection from low-level background colonisation.

DEVELOPMENT PLAN: The research will be conducted in four distinct phases, linked by pivotal stop/go points (Fig. 3 and 8). Phase 1 will build upon our existing data and resources to drive the iterative development of dressings and an optimised prototype. Phase 2: i) Will determine toxicological profiles and compliance with ISO10993; ii) Clinical feasibility study (using wound swabs / exudates) to ensure performance is at least comparable to existing gold standard microbiological assays. Phase 3 will see completion of toxicology and clinical feasibility studies, followed by technology transfer (phase 4) and trials of scale-up manufacture and packaging at our industry partner Paul Hartmann AG. Ultimately this will deliver a product ready for production and full clinical testing.

CLINICAL NEED
There is a clear and unmet clinical need in burn wound care for tools that allow: i) Detection of infection at point of care (PoC); ii) Early diagnosis of infection to permit the most effective intervention; iii) Clear identification of wounds in which the Critical Colonization Threshold (CCT) of bacteria has been reached; iv) Differentiate between symptoms relating to wound infection and those due to injury-related inflammation.

IMPACT and SCALE OF THE PROBLEM
Over 140,000 people in England and Wales suffer burn injuries every year, with ~50,000 requiring treatment at specialised burn centres, and ~13,000 admitted to hospital. A major problem in the care of these patients is infection, to which patients with burn injuries are particularly vulnerable. An estimated 18% of burn patients acquire infection-related complications - a major cause of morbidity, mortality and increased cost of care. In addition to aggressive antibiotic therapy, treatment typically necessitates the removal of dressings, and sometimes further surgery. This significantly increases the probability of scarring and undermines clinical outcomes, resulting in a subsequent life-long psychological burden to the patient. Failure to treat patients in a timely manner also increases overall morbidity and mortality rates. Infection also greatly increases treatment costs with in patient stays costing ~£264.12 per day, dressing changes ~£250 per change, and surgical time at ~£500 per hour (Data from QVH & BRHC).

Over management is believed to be a key clinical problem in these patients. Symptoms resulting from the normal immunological response to the burn injury itself are often similar to those encountered when infection is present, but are often present in the absence of infection. However, the seriousness of infection in burns patients forces clinicians to treat presumptively, often leading to over-treatment, and a significant level of inappropriate antibiotic usage. The comparatively high levels of antibiotics required to achieve inhibitory levels in the wound bed compound the latter, and promote the emergence of antimicrobial-resistant (AMR) strains.

Surveillance and diagnosis of infection is therefore a critical aspect of burn wound management. The capacity for clinicians to deliver this aspect of care has far-reaching implications for patient welfare, but is a significant challenge with currently available tools. At present, the diagnosis of infection in burns patients is impossible at PoC, with commonly used biomarkers of infection of limited value, and diagnosis predominantly based on subjective clinical judgement. Subsequent confirmatory tests (microbiological culture) to identify causative pathogens typically require several days, and do not distinguish between sub-clinical colonization and clinically relevant infection (see below). The WHO have highlighted that improved diagnostics are a key weapon in the fight against AMR.